Triazolopyridines and triazolopyrazines as LSD1 inhibitors

• US 10,138,249 B2
• Filed: 08/07/2017
• Issued: 11/27/2018
• Est. Priority Date: 07/10/2014
• Status: Active Grant

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Original Assignee: Incyte Corporation
• Inventors: Wu, Liangxing, Wang, Xiaozhao, Yao, Wenqing, Zhang, Colin
• Primary Examiner(s): Rahmani, Niloofar
• Application Number:
  US15/670,094
• Publication Number:
  US 20170362245A1
• Time in Patent Office: 477 Days
• Field of Search: 514300, 514303, 546119, 546121
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention is directed to [1,2,4]triazolo[4,3-a]pyridine and [1,2,4]triazolo[4,3-a]pyrazine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

Claims

1. A method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of Formula IVa:

2. The method of claim 1 wherein said hematological cancer is selected from acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), and multiple myeloma.

3. The method of claim 1, wherein R^Z is H, C_1-4 alkyl, or C_1-6 haloalkyl, wherein said C_1-4 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, CN, F, phenyl, C_3-7 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C(O)NH₂, phenoxy, and dimethylamino, wherein said phenyl is optionally substituted by CN and said 5-6 membered heteroaryl is optionally substituted by methyl.

4. The method of claim 1, wherein R^Z is H, methyl, cyanomethyl, cyanoethyl, cyclopentylmethyl, tetrahydrofuranylmethyl, (1-methyl-1H-pyrazol-3-yl)methyl, morpholinylethyl, aminocarbonylmethyl, 3,3,3-trifluoro-2-hydroxypropyl, piperidinylmethyl, phenoxyethyl, dimethylaminoethyl, benzyl, cyanophenyl, or hydroxyethyl.

5. The method of claim 1, wherein R^A is CN.

6. The method of claim 1, wherein R^B is C_1-6 alkyl.

7. The method of claim 1, wherein R^B is methyl.

8. The method of claim 1, wherein each R^a1 is pyrrolidinylmethyl.

9. The method of claim 1, wherein Cy⁴ is phenyl, cyclopentyl, tetrahydrofuranyl, pyrazolyl, morpholinyl, or piperidinyl, each optionally substituted by one substituent independently selected from methyl and CN.

10. The method of claim 1, wherein Cy⁵ is pyrrolidinyl.

11. The method of claim 1, wherein the compound is selected from:

4-{5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-{2-methyl-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

(R)-4-(2-(cyanomethyl)-3-oxo-8-(pyrrolidin-3-ylmethoxy)-5-p-tolyl-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzonitrile;

4-{2-(2-cyanoethyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-{2-(cyclopentylmethyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-[5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2-(tetrahydrofuran-2-ylmethyl)-2, 3-dihydro[1,2,4]triazolo[4, 3-a]pyridin-6-yl]benzonitrile;

4-{5-(4-methylphenyl)-2-[(1-methyl-1H-pyrazol-3-yl)methyl]-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2, 3-dihydro [1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-{5-(4-methylphenyl)-2-(2-morpholin-4-ylethyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

2-[6-(4-cyanophenyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy][1, 2,4]triazolo [4,3-a]pyridin-2(3H)-yl]acetamide;

4-[5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro [1,2,4]triazolo[4,3-a]pyridin-6-yl]benzonitrile;

4-{5-(4-methylphenyl)-3-oxo-2-(piperidin-4-ylmethyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-{5-(4-methylphenyl)-3-oxo-2-(2-phenoxyethyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-{2-[2-(dimethylamino)ethyl]-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-{2-benzyl-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-{2-(4-cyanobenzyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

4-{2-(2-hydroxyethyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;

or a pharmaceutically acceptable salt of any of the aforementioned.

12. The method of claim 1, wherein n is 1 or 2.

13. The method of claim 1, wherein m is 1, 2, 3, or 4.

14. The method of claim 1, wherein m is 1 or 2.

15. The method of claim 1, wherein the hematological cancer is acute myelogenous leukemia (AML).

16. The method of claim 1, wherein the cancer is lung cancer.

17. The method of claim 16, wherein the lung cancer is selected from non-small cell lung cancer (NSCLC), bronchogenic carcinoma, alveolar carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

18. The method of claim 16, wherein the lung cancer is selected from squamous cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma.

19. The method of claim 16, wherein the lung cancer is undifferentiated small cell lung cancer.

20. The method of claim 1, wherein the hematological cancer is primary myelofibrosis (PMF).

21. The method of claim 1, wherein the sarcoma is Ewing'"'"'s sarcoma.